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Review
. 2024 Dec;398(3):161-173.
doi: 10.1007/s00441-024-03926-2. Epub 2024 Oct 22.

Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression

Emanuela Chiarella  1
Affiliations
Review

Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression

Emanuela Chiarella. Cell Tissue Res. 2024 Dec.

Abstract

Hematopoietic stem cells (HSCs) drive cellular turnover in the hematopoietic system by balancing self-renewal and differentiation. In the adult bone marrow (BM), these cells are regulated by a complex cellular microenvironment known as "niche," which involves dynamic interactions between diverse cellular and non-cellular elements. During blood cell maturation, lineage branching is guided by clusters of genes that interact or counteract each other, forming complex networks of lineage-specific transcription factors. Disruptions in these networks can lead to obstacles in differentiation, lineage reprogramming, and ultimately malignant transformation, including acute myeloid leukemia (AML). Zinc Finger Protein 521 (Znf521/Zfp521), a conserved transcription factor enriched in HSCs in both human and murine hematopoiesis, plays a pivotal role in regulating HSC self-renewal and differentiation. Its enforced expression preserves progenitor cell activity, while inhibition promotes differentiation toward the lymphoid and myeloid lineages. Transcriptomic analysis of human AML patient samples has revealed upregulation of ZNF521 in AMLs with the t(9;11) fusion gene MLL-AF9. In vitro studies have shown that ZNF521 collaborates with MLL-AF9 to enhance the growth of transformed leukemic cells, increase colony formation, and activate MLL target genes. Conversely, inhibition of ZNF521 using short-hairpin RNA (shRNA) results in decreased leukemia proliferation, reduced colony formation, and induction of cell cycle arrest in MLL-rearranged AML cell lines. In vivo experiments have demonstrated that mZFP521-deficient mice transduced with MLL-AF9 experience a delay in leukemia development. This review provides an overview of the regulatory network involving ZNF521, which plays a crucial role in controlling both HSC self-renewal and differentiation pathways. Furthermore, we examine the impact of ZNF521 on the leukemic phenotype and consider it a potential marker for MLL-AF9+ AML.

Keywords: Acute myeloid leukemia (AML); Hematopoietic stem cells (HSCs); MLL-AF9 fusion gene; Myeloid and lymphoid differentiation; Transcription factors; Znf521/Zfp521; t (9;11).

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Conflict of interest statement

Declarations. Ethics approval: Not applicable. Informed consent: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Framework of the hematopoietic hierarchy. Hematopoietic stem cells are characterized by its ability to self-renew and to differentiate into all types of hematopoietic cells (multipotency). During the differentiation process, an HSC initially loses its self-renewal capacity. Subsequently, it gradually loses its potential to differentiate into various lineages, committing step-by-step to become a mature, functional cell of a specific lineage
Fig. 2
Fig. 2
The bone marrow niches housing hematopoietic stem cells (HSCs) constitute a complex and dynamic molecular network of interactions involving multiple cell types, including endothelial cells, mesenchymal stromal cells, osteoblasts, osteoclasts adipocytes, neuroglial cells, and mature hematopoietic cells. In bone marrow niches, hematopoietic stem cells (HSCs) maintain their self-renewal capacity, thanks to a pool of chemokines, including CXCL12 and SCF, which are produced by mesenchymal progenitors and endothelial cells
Fig. 3
Fig. 3
Schematic representation of the ZNF521/ZFP521 gene and its protein. a The ZNF521 gene, located on human chromosome 18 at the 18q11.2 region, spans 290 Kb. b Its mRNA is 4869 nucleotides long and consists of eight exons. c The Znf521/Zfp521 protein is characterized by the following features: 30 C2H2 zinc fingers distributed throughout the protein, a nuclear remodeling and histone deacetylation complex (NuRD) motif located at the N-terminal end, and a putative nuclear localization signal positioned between ZF8 and ZF9
Fig. 4
Fig. 4
ZNF521/ZFP521 promotes MLL-AF9 leukemogenesis in human and mouse hematopoietic stem cells. a Enforced expression of ZNF521 sustains cell expansion, increases the number of colony-forming cells, and activates MLL target genes in primary MLL-AF9-modified hematopoietic stem cells as well as in hematopoietic cell lines (THP-1 and NOMO-1). b The deficiency of Zfp521 caused a significant delay in mortality among both primary and secondary transplant recipients
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References

    1. Abdel-Aziz AK (2023) Advances in acute myeloid leukemia differentiation therapy: a critical review. Biochem Pharmacol 215:115709. 10.1016/J.BCP.2023.115709 - PubMed
    1. Addison WN, Fu MM, Yang HX et al (2014) Direct transcriptional repression of Zfp423 by Zfp521 mediates a bone morphogenic protein-dependent osteoblast versus adipocyte lineage commitment switch. Mol Cell Biol 34:3076–3085. 10.1128/MCB.00185-14 - PMC - PubMed
    1. Al Dallal S, Wolton K, Hentges KE (2016) Zfp521 promotes B-cell viability and cyclin D1 gene expression in a B cell culture system. Leuk Res 46:10–17. 10.1016/J.LEUKRES.2016.03.013 - PMC - PubMed
    1. Barisas DAG, Choi K (2024) Extramedullary hematopoiesis in cancer. Exp Mol Med 56(3):549–558. 10.1038/s12276-024-01192-4 - PMC - PubMed
    1. Bernaudo F, Monteleone F, Mesuraca M et al (2015) Validation of a novel shotgun proteomic workflow for the discovery of protein-protein interactions: focus on ZNF521. J Proteome Res 14:1888–1899. 10.1021/PR501288H - PubMed

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